Title A new intermediate in the Prins reaction. Issue Date ...repository.kulib.kyoto-u.ac.jp/dspace/bitstream/... · Title A new intermediate in the Prins reaction. Author(s) Yamabe,

Title A new intermediate in the Prins reaction

Author(s) Yamabe Shinichi Fukuda Takeshi Yamazaki Shoko

Citation Beilstein journal of organic chemistry (2013) 9 476-485

Issue Date 2013-03-05

URL httphdlhandlenet2433173363

copy 2013 Yamabe et al licensee Beilstein-Institut This is anOpen Access article under the terms of the Creative CommonsAttribution License(httpcreativecommonsorglicensesby20) which permitsunrestricted use distribution and reproduction in any mediumprovided the original work is properly citedThe license is subject to the Beilstein Journal of OrganicChemistry terms and conditions (httpwwwbeilstein-journalsorgbjoc)

Type Journal Article

Textversion publisher

Kyoto University

A new intermediate in the Prins reactionShinichi Yamabe1 Takeshi Fukuda2 and Shoko Yamazaki2

Full Research Paper Open Access

Address1Fukui Institute for Fundamental Chemistry Kyoto UniversityTakano-Nishihiraki-cho 34-4 Sakyou-ku Kyoto 606-8103 Japan and2Department of Chemistry Nara University of EducationTakabatake-cho Nara 630-8528 Japan

EmailShinichi Yamabe - yamabesfukuikyoto-uacjp

Corresponding author

KeywordsDFT calculations hemiacetal intermediate hydrogen bond Prinsreaction transition state

Beilstein J Org Chem 2013 9 476ndash485doi103762bjoc951

Received 14 November 2012Accepted 31 January 2013Published 05 March 2013

This article is part of the Thematic Series New reactive intermediates inorganic chemistry

Guest Editor G Bucher

copy 2013 Yamabe et al licensee Beilstein-InstitutLicense and terms see end of document

AbstractTwo Prins reactions were investigated by the use of DFT calculations A model composed of RndashCH=CH2 + H3O+(H2O)13 +

(H2C=O)2 R = Me and Ph was adopted to trace reaction paths For both alkenes the concerted path forming 13-diols was

obtained as the rate determining step (TS1) TS stands for a transition state From the 13-diol a bimolecular elimination (TS2)

leads to the allylic alcohol as the first channel In the second channel the 13-diol was converted via TS3 into an unprecedented

hemiacetal intermediate HOndashCH2ndashOndashCH(R)ndashCH2ndashCH2ndashOH This intermediate undergoes ring closure (TS4) affording the 13-

dioxane product The intermediate is of almost the same stability as the product and two species were suggested to be in a state of

equilibrium While the geometry of TS1 appears to be forwarded to that of a carbocation intermediate the cation disappeared

through the enlargement of the water cluster Dynamical calculations of a classical trajectory using the atom-centered density

matrix propagation molecular dynamics model on the four TSs were carried out and results of IRC calculations were confirmed

by them

IntroductionThe Prins reaction is the acid-catalyzed addition of aldehydes to

alkenes and gives different products depending on the reaction

conditions The first work on the condensation of alkenes with

aldehydes was made by Kriewitz in 1899 [1] He found that

unsaturated alcohols were produced when pinene (a bicyclic

monoterpene) was heated with paraformaldehyde However

Prins performed the first rather comprehensive study of the

reactions between formaldehyde and hydrocarbons with C=C

double bonds [23] These were styrene pinene camphene and

anethole As a catalyst sulfuric acid was used and water or

glacial acetic acid was the solvent A general Prins reaction is

shown in Scheme 1

A typical Prins reaction is exhibited in Scheme 2 [4] Here the

six-membered ring compound 44-dimethyl-13-dioxane is the

major product along with 3-methyl-13-butane-diol The 13-

dioxane is hydrolyzed to form the 13-diol by stirring the former

in a 2 (or lower) sulfuric acid solution under reflux [4]

Beilstein J Org Chem 2013 9 476ndash485

Scheme 1 A general scheme of the Prins reaction

Scheme 2 An example of the Prins reaction [4] The product yields () are based on formaldehyde

Scheme 3 An equilibrium in the hydrolysis of the product 13-dioxane

However the hydrolysis yield on the dioxane charged is only

8ndash17 depending on the alkene reactants The result was inter-

preted in terms of a reversible reaction shown in Scheme 3

On the other hand a reaction of longifolene with formaldehyde

in acetic acid yielded the acetate of an allylic alcohol (ω-acet-

oxymethyl longifolene) as a major product under high-tempera-

ture conditions (Scheme 4 140 degC 24 h) [5]

A scheme was proposed as to the mechanism of the Prins reac-

tions [6-18] to afford 13-dioxane 13-diol and allylic alcohol

where the carbocation intermediate (X) is included (Scheme 5)

In the second step X is formed From X two routes (i) and (ii)

are possible In the route (i) a water molecule is linked with the

cation center which leads to formation of the 13-diol and the

subsequent allylic alcohol In (ii) the second H2C=O is bound

Scheme 5 A reaction mechanism involving the carbonium-ion intermediate X

Scheme 4 Formation of the acetate of an allylic alcohol by Prins reac-tion [5]

to the cation center leading to formation of the 13-dioxane

While tertiary carbocations might intervene the presence or

absence of secondary ones would be critical in the aqueous

media This is because the water cluster has high nucleophilic

strength and tends to make CndashO bonds to form alcohols over-

coming the intervention of carbocations In this respect the

mechanism depicted in Scheme 5 needs to be examined by the

use of some alkenes theoretically

A variety of protic acids and Lewis acids are employed to

catalyze the reaction and Prins-type reactions have found

numerous synthetic applications [619-25] In spite of the exten-

sive experimental studies there have been no computational

studies of the classic Prins reaction The reaction is also impor-

tant because the constituent atoms are only C H and O in the

original system and it is a fundamental organic reaction In this

work as the first attempt reactions paths were traced by DFT

calculations under Prinsrsquo original conditions (styrene and

formaldehyde in the acidic aqueous media) As an alkene

propene was also employed for comparison From styrene

4-phenyl-13-dioxane was obtained in 86 yield and from

propene 4-methyl-13-dioxane in 65 yield (based on H2C=O)

[4] The target of this work is to check whether the seemingly

established mechanism shown in Scheme 5 holds for the two

alkenes and the expected steps in Scheme 5 are obtained by

DFT calculations

Method of calculationsThe reacting systems were investigated by density functional

theory calculations The B3LYP method [2627] was used for

geometry optimizations In order to check the reliability of

B3LYP M06-2X [28] and a dispersion correction method

(ωB97XD [29]) were applied to the rate-determining step of the

propene reaction TS1(Me) The basis sets employed were

6-31G(d) and 6-311+G(dp) Transition states (TSs) were

sought first by partial optimizations at bond interchange

regions Second by the use of Hessian matrices TS geometries

were optimized They were characterized by vibrational

analysis which checked whether the obtained geometries have

single imaginary frequencies (νDaggers) From the TSs reaction paths

were traced by the intrinsic reaction coordinate (IRC) method

[3031] to obtain the energy-minimum geometries Relative

energies ΔE were obtained by single-point calculations of

RB3LYP6-311+G(dp) [self-consistent reaction field (SCRF) =

PCM [32-34] solvent = water] on the RB3LYP6-31G(d) and

6-311+G(dp) geometries and their ZPE ones Here ZPE

denotes the zero-point vibrational energy

In order to confirm the obtained TS characters dynamical

calculations of a classical trajectory calculation using the atom-

centered density matrix propagation molecular dynamics

(ADMP) model [35-37] on TSs were carried out Geometries of

the TSs at 2000 steps of 01 femtoseconds (10minus15 seconds) were

determined

All the calculations were carried out by using the GAUSSIAN

09 [38] program package The computations were performed at

the Research Center for Computational Science Okazaki

As for the model alkene two H2C=O and H3O+ molecules are

needed to simulate the paths depicted in Scheme 5 In addition

to them 13 H2O molecules are included as shown in Scheme 6

In the model H2C=O catalyzed by H3O+ (a) works as an elec-

trophile to add to the alkene The addition follows Markowni-

koffs rule [39] H2O (f) is the nucleophile to the left-hand

carbon of the alkene One proton of H2O (f) moves to H2O (h)

upon the addition and this becomes a hydronium ion Around

the newly formed ion six H2O molecules (i j k l m and n)

are located At the same time toward the carbonyl oxygen of

the central H2C=O a proton is moved from H3O+ (a) To this

ion H2O (c) and H2O (d) are attached H2O (b) and H2O (e) are

coordinated to the second sp2 lone-pair orbitals of two H2C=O

molecules

Scheme 6 A reaction model composed of RHC=CH2 (H2C=O)2 andH3O+(H2O)13 to obtain the path of step 2 (Scheme 5) H3O+ and H2Oare labeled with (a) (b) (c) hellip (n) to explain their positions

Results and DiscussionThe propene reactionFigure 1 shows precursor and TS geometries in a Prins reaction

of propene In precursor (Me) while two H2C=O molecules are

linked with water ones via hydrogen bonds hydrophobic

propene is outside them When it is put into the water cluster

the first transition state [TS1(Me)] is brought about Worthy of

note is that various concomitant bond interchanges are involved

in TS1(Me) The reaction center is at the C(1)C(5) bond and

simultaneously the incipient C(6)O(14) bond is formed After

TS1(Me) not the carbonium ion but rather the butane-13-diol

diol(Me) is afforded This result demonstrates that steps 1 2

and 3 in Scheme 5 occur at the same time without intervention

of the carbocation X From diol(Me) two TSs were obtained

One is TS2(Me) leading to the allylic alcohol 2-buten-1-ol

here called ene-ol(Me) The other is TS3(Me) leading to an in-

termediate not included in Scheme 5 This species 3-(hydrox-

ymethoxy)-1-butanol called here ether(Me) has an ether

moiety and is a hemiacetal Generally these are formed by the

formal addition of an alcohol to the carbonyl group In this case

13-diol(Me) is the alcohol and the second formaldehyde is of

the C=O group Closure of the six-membered ring from the

ether(Me) [TS4(Me)] gives the product 4-methyl-13-dioxane

dioxane(Me) Thus the obtained route (ii) precursor (Me) rarr

diol(Me) rarr ether(Me) rarr dioxane(Me) is different from that in

Scheme 5 The first difference is the absence of the carbocation

X in the former route The second one is a new hemiacetal in-

termediate ether(Me)

Geometries in Figure S1 (Supporting Information File 1) were

obtained by IRC calculations starting from TS ones in Figure 1

In order to confirm the route depicted in Figure 1 ADMP

dynamical calculations from TSs were also performed Geome-

tries after 200 femtosecond from TS1(Me) TS2(Me) TS3(Me)

and TS4(Me) are shown as ADMP1(Me) ADMP2(Me)

ADMP3(Me) and ADMP4(Me) respectively in Figure S2

(Supporting Information File 1) These were found to be similar

to diol(Me) ene-ol(Me) ether(Me) and dioxane(Me) in Figure

S1 respectively Thus those TSs were confirmed to be in the

reaction channel

Figure 2 exhibits geometry-dependent energy changes for the

transition states depicted in Figure 1 and Figure S1 TS1(Me)

was found to be the rate-determining step The butane-13-diol

diol(Me) is the first stable intermediate (Δ(ET + ZPE) =

minus1877 kcalmol) From diol(Me) two TSs TS2(Me) and

TS3(Me) were obtained TS3(Me) leading to the hemiacetal in-

termediate ether(Me) is much more likely than TS2(Me)

leading to the allylic alcohol ene-ol(Me) In fact the latter is

not formed under the reaction conditions in Scheme 2

The hemiacetal intermediate ether(Me) is remarkably stable

Figure 1 Geometries of the precursor and the transition states (TSs) of the Prins reaction of propene with (formaldehyde)2 and H3O+(H2O)13according to the model of Scheme 6 Sole imaginary frequencies νDaggers verifying that the obtained geometries are at saddle points are also shownThose of intermediates and products are exhibited in Figure S1 of Supporting Information File 1 (Me) denotes the propene (RndashHC=CH2 R = Me)reaction Distances and imaginary frequencies by B3LYP6-31G(d) and B3LYP6-311+G(dp) (in square brackets) are shown Underlined numbersare by M06-2X and those in braces by ωB97XD for TS1(Me)

(Δ(ET + ZPE) = minus3074 kcalmol) The stability is almost the

same as that of the product dioxane(Me) (Δ(ET + ZPE) =

minus3137 kcalmol) This energetic result suggests that both the

ether(Me) and dioxane(Me) are products in the propene Prins

reaction whereas the ether(Me) species has not been reported

so far

Figure 2 Energy changes (in kcalmol) of the propene Prins reaction calculated by B3LYP6-311+G(dp) SCRF=(PCM solvent = mwater) B3LYP6-31G(d) ZPE The corresponding geometries are shown in Figure 1 and Figure S1 ET stands for the total energy At TS1(Me) while B3LYP6-311+G(dp) SCRF=PCM and M06-2X6-311+G(dp) SCRF=PCM energies are similar the ωB97XD6-311+G(dp) SCRF=PCM energy seems to beoverestimated in spite of the similarity of the three geometries in Figure 1

The styrene reactionFigure 3 shows geometries of four TSs and Figure S3 shows

those of precursor(Ph) diol(Ph) ene-ol(Ph) ether(Ph) and

dioxane(Ph) Geometric changes similar to those of the propene

Prins reaction were obtained ie precursor(Ph) rarr TS1(Ph) rarr

diol(Ph) [rarr TS2(Ph) rarr ene-ol(Ph)] rarr TS3(Ph) rarr ether(Ph)

rarr TS4(Ph) rarr dioxane(Ph) Different from the reaction pattern

shown in Scheme 5 the cation center is at H3O+ in the inter-

mediates and product At TS1(Ph) the incipient C(6)O(14)

bond distance (= 3138 Aring) is extraordinarily larger than the

standard one (ca 185 Aring) for the CO-forming TS For

instance it was calculated to be 1833 1879 Aring in the first TS

of the acid-catalyzed hydrolysis of ethyl acetate by B3LYP6-

31G(d) M062X6-311G(dp) in our recent work [40]

Through the B3LYP6-311+G(dp) geometry optimization

TS1(Ph) was obtained as the carbocation (X) formation TS

shown in Figure S4 Here the C(6)O(14) formation is not

involved and the concerted diol(Ph)-formation TS could not be

obtained The character of TS1(Ph) needs to be investigated in

more detail and will be discussed in the next subsection

Figure 4 shows the energy changes of the styrene Prins reaction

They are compared with those of the propene Prins reaction

(Figure 2) The rate determining step is again TS1(Ph) A

noticeable difference is found in the contrast of the stability

order ene-ol(Ph) gt ether(Ph) versus ene-ol(Me) lt ether(Me)

The 3-phenyl-2-propenol (cinnamyl alcohol) is an allylic

alcohol with the π conjugation of the phenyl ring and is thought

to be the source of the stability of ene-ol(Ph) However

TS2(Ph) has a large activation energy +1804 kcalmol Thus

while ene-ol(Ph) is thermodynamically favorable it is unfavor-

able kinetically The energy of ether(Ph) minus1240 kcalmol is

again similar to that of dioxane(Ph) minus1112 kcalmol Both

ether(Ph) and dioxane(Ph) may be regarded as products of the

styrene Prins reaction In this respect the equilibrium depicted

in Scheme 3 is not for the (dioxanendashdiol) pair but for the

(dioxanendashether) pair The product 13-dioxane may be obtained

with aid of the hygroscopy of the 45minus55 sulfuric acid The

water is taken off by H2SO4 and according to Le Chateliers

principle the equilibrium is shifted toward the dioxane side

Formation of the 13-diol in Scheme 3 would arise not from the

equilibration with the dioxane but from the high-temperature

reflux conditions for the endothermic step ie ether rarr

13-diol

The carbocation intermediate (X)In the Prins reaction of styrene it is critical whether the first

transition state leads to diol(Ph) or to the carbocation X(Ph)

The intervention of X(Ph) was examined by an extended model

shown in Figure S5 In the model the initial geometry for the

optimization was made of that of X(Ph) in Figure S4 and seven

additional water molecules (atom numbers from 68 to 88)

Through the optimization by B3LYP6-31G(d) and B3LYP6-

311+G(dp) the initial carbocation was found to be converted to

the 13-diol as shown in the lower side of Figure S5 Thus the

carbocation would intervene when the size of the water cluster

surrounding the reactants (alkene and formaldehyde) is small

While this condition corresponds to the reaction in a binary

solvent such as acetonendashwater the reaction in aqueous media

would not involve the carbocation X

Figure 3 Geometries of the transition states (TSs) of the Prins reaction of styrene + (formaldehyde)2 + H3O+(H2O)13 Those of intermediates andproducts are exhibited in Figure S3 of Supporting Information File 1 (Ph) denotes the styrene (RndashHC=CH2 R = phenyl) reaction The geometry ofTS1(Ph) by B3LYP6-311+G(dp) is shown in Figure S4 as TS1rsquo(Ph)

Dependence of the number of water molecules on the geome-

tries of TS1(Ph) was investigated by the use of two extended

models styrene + H3O+(H2O)n + (H2C=O)2 (n = 20 and 30)

The n = 13 TS1(Ph) is shown in Figure 3 The n = 20 and 30

TS1(Ph) geometries are shown in Figure 5

While the central part of the n = 20 geometry is similar to that

of the n = 13 one the incipient O(14)C(6) bond in the

n = 30 TS1(Ph) is shorter (2692 Aring) than those of the n = 13 and

n = 20 TSs This result indicates that the extended model of the

n = 30 TS1(Ph) expresses clearly the 13-diol formation

Figure 4 Energy changes (in kcalmol) of the styrene Prins reaction calculated by B3LYP6-311+G(dp) SCRF = (PCM solvent = water) B3LYP6-31G(d) ZPE The corresponding geometries are shown in Figure 3 and Figure S3

Figure 5 TS1(Ph) geometries of n = 20 and n = 30 in the reacting system of styrene + H3O+(H2O)n + (H2C=O)2 calculated by B3LYP6-31G(d)

ConclusionIn this work two Prins reactions were investigated by the use of

B3LYP calculations A model composed of RndashCH=CH2 +

H3O+(H2O)13 + (H2C=O)2 R = Me and Ph was employed to

trace reaction paths The result is summarized in Scheme 7

Scheme 7 Summary of the present calculated results The ether inthe box is the new intermediate found in this work The blue line standsfor the newly formed covalent bond at each step

The 13-diol is formed concertedly in the rate-determining step

TS1 From the diol the ene-ol is afforded in the E2 (bimolec-

ular elimination TS2) pathway Most likely the addition (TS3)

of the second formaldehyde to the 13-diol leads to the new in-

termediate (ether or hemiacetal) Ring closure from the ether

gives the product 13-dioxane The 13-dioxane is in equilib-

rium with the ether

It is critical whether TS1 goes to the 13-diol or to the carbocat-

ion X While the intervention is suggested to depend on the

concentration of water in aqueous media the cation is unlikely

owing to the high nucleophilicity of the large water cluster

Supporting InformationSupporting Information File 1Geometries of the precursor intermediates and products

and other related geometries

[httpwwwbeilstein-journalsorgbjoccontent

supplementary1860-5397-9-51-S1pdf]

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License and TermsThis is an Open Access article under the terms of the

Creative Commons Attribution License

(httpcreativecommonsorglicensesby20) which

permits unrestricted use distribution and reproduction in

any medium provided the original work is properly cited

The license is subject to the Beilstein Journal of Organic

Chemistry terms and conditions

(httpwwwbeilstein-journalsorgbjoc)

The definitive version of this article is the electronic one

which can be found at

doi103762bjoc951

Abstract

Introduction

Method of calculations

Results and Discussion

The propene reaction

The styrene reaction

The carbocation intermediate (X)

Conclusion

Supporting Information

References